Serotonin 5-HT3, receptor partial activator

Abstract

This invention provides a serotonin 5-HT3 receptor partial activator which has a serotonin 5-HT3 receptor activating action, in addition to its serotonin 5-HT3 receptor antagonism, and does not cause constipation as a side effect. Particularly, based on the finding that newly synthesized benzoxazole derivatives typified by the compounds of the following formula (2) have strong serotonin 5-HT3 receptor antagonism and serotonin 5-HT3 receptor activating action, this invention provides these benzoxazole derivatives as serotonin 5-HT3 receptor partial activators.In the above formula, R1 to R4 may be the same or different from one another and each represents a hydrogen atom, a halogen atom, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted lower alkenyl group or a substituted or unsubstituted amino group, or two groups of R1 and R2 may be linked together to form a ring structure, namely benzene ring; R5 represents a hydrogen atom, a substituted or unsubstituted lower alkyl group or a substituted or unsubstituted lower alkenyl group; and m is an integer of 1 to 4.

What is claimed is:  
     
       1. A method for treating irritable colon syndrome, which comprises the step of administering to a subject in need of treatment a pharmaceutically effective amount of a pharmaceutical composition which comprises, as its active ingredient, the compound represented by formula (2):                    
       wherein R 1  to R 4  are the same or different from one another and each represents a hydrogen atom, a halogen atom, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted lower alkenyl group or a substituted or unsubstituted amino group, or two groups of R 1  and R 2  are linked together to form a benzene ring and R 3  and R 4  are hydrogen atoms, with the proviso that compounds in which all of R 1  to R 4  are hydrogen atoms are excluded; R 5  represents a hydrogen atom; and m is an integer of 2, in which said lower alkyl group means a straight or branched C 1 -C 4  alkyl group, said lower alkenyl group means a straight or branched C 2 -C 4  alkenyl group, the substituent for said lower alkyl or lower alkenyl group is selected from the group consisting of a halogen atom, a hydroxyl group, a carbamoyl group, an amino group and a cyano group, the substituent for said amino group is selected from the group consisting of a straight or branched C 1 -C 4  alkyl group, a straight or branched C 1 -C 4  alkycarbonyl group, a straight or branched C 2 -C 4  alkenyl group and a benzylidene group which may have a phenyl group, and said halogen atom is selected from the group consisting of fluorine, chlorine, bromine and iodine atoms.  
     
     
       2. A pharmaceutical composition which comprises, as its active ingredient, the compound represented by formula (2):                    
       wherein R 1  to R 4  are the same or different from one another and each represents a hydrogen atom, a halogen atom, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted lower alkenyl group or a substituted or unsubstituted amino group, or two groups of R 1  and R 2  are linked together to form a benzene ring and R 3  and R 4  are hydrogen atoms, with the proviso that compounds in which all of R 1  to R 4  are hydrogen atoms are excluded; R 5  represents a hydrogen atom; and m is an integer of 2, in which said lower alkyl group means a straight or branched C 1 -C 4  alkyl group, said lower alkenyl group means a straight or branched C 2 -C 4  alkenyl group, the substituent for said lower alkyl or lower alkenyl group is selected from the group consisting of a halogen atom, a hydroxyl group, a carbamoyl group, an amino group and a cyano group, the substituent for said amino group is selected from the group consisting of a straight or branched C 1 -C 4  alkyl group, a straight or branched C 1 -C 4  alkylcarbonyl group, a straight or branched C 2 -C 4  alkenyl group and a benzylidene group which may have a phenyl group, and said halogen atom is selected from the group consisting of fluorine, chlorine, bromine and iodine atoms,  
       and which further comprises a pharmaceutically acceptable carrier.  
     
     
       3. The pharmaceutical composition according to claim  2 , wherein R 1  to R 4  in the formula (2) are the same or different from one another and each represents a hydrogen atom, a halogen atom or a substituted or unsubstituted lower alkyl group, or two groups of R 1  and R 2  are optionally linked together to form a benzene ring. 
     
     
       4. The pharmaceutical composition of claim  2 , wherein at least two of R 1  to R 4  each independently represents a halogen atom or a substituted or unsubstituted lower alkyl group and the remaining groups are hydrogen atoms.